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Journal ArticleDOI

Evaluation of the renal toxicity of heme proteins and their derivatives: a role in the genesis of acute tubule necrosis.

01 Mar 1970-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 131, Iss: 3, pp 443-460
TL;DR: It is concluded that heme proteins play a role in tubule dysfunction seen in acute tubule necrosis, and other factors known to play a part in the pathogenesis of this renal syndrome are collated.
Abstract: This investigation studies the toxicity of heme proteins and/or their break-down products on renal function. Heme proteinemia precedes acute tubule necrosis at a frequency great enough to suggest a causal relationship between the two events. Physiological and metabolic functions of kidney slices are investigated in several models of acute tubule necrosis. Organic acid and organic base transport is depressed earliest. These alterations in tubule function cannot be explained by ischemia or obstruction alone. Heme proteinemia in rats or incubation of renal slices in medium containing heme proteins yields several interesting observations. Neither in vivo or in vitro do hemoglobin and methemoglobin alone produce a depressive effect on the transport systems studied. However, parallel to many clinical situations, when such secondary insults as hypoxia and elevated ammonia concentrations are included in the experimental design, transport functions are depressed. Ferrihemate, a molecule smaller than hemoglobin or methemoglobin, depresses transport function without secondary insults. From these studies it is concluded that heme proteins play a role in tubule dysfunction seen in acute tubule necrosis. A model is presented that collates these data with other factors known to play a part in the pathogenesis of this renal syndrome.

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Journal ArticleDOI
TL;DR: The complications of rhabdomyolysis are preventable and the syndrome has a good prognosis; hemodialysis should be considered when life-threatening hyperkalemia and metabolic acidosis exist.

226 citations

Journal ArticleDOI
TL;DR: This study describes representative recent cases of rhabdomyolysis induced by influenza from an institution and details the wide variety of infections that can cause muscle damage.
Abstract: Rhabdomyolysis can be precipitated by trauma, ischemia, metabolic defects, electrolyte abnormalities, drugs, and a wide variety of infectious diseases. At our institution, recent cases of rhabdomyolysis induced by influenza prompted us to review the infectious etiologies of this entity. In addition, a thorough literature search revealed numerous case reports but no general review on this subject. This study describes representative recent cases from our institution and details the wide variety of infections that can cause muscle damage. The pathophysiological mechanisms, muscle histology, and correlation with renal dysfunction are also discussed.

204 citations


Cites background from "Evaluation of the renal toxicity of..."

  • ...Cortical ischemia and decreased glomerular filtration are also injurious, and when these conditions are combined with hypovolemia, oliguric renal failure can result [70, 71]....

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Journal ArticleDOI
TL;DR: The present state of knowledge of clinical and biochemical diagnosis of rhabdomyolysis, the pathophysiologic background, the classification and the etiological provocative factors are reviewed.

184 citations

Journal ArticleDOI
TL;DR: The causes, clinical presentation, and prevalence of acute renal failure in pediatric rhabdomyolysis with the published data for adults are compared, and the relationship of acute kidney failure with treatment modalities such as fluid and bicarbonate administration is explored.
Abstract: OBJECTIVES. The goals were to (1) compare the causes, clinical presentation, and prevalence of acute renal failure in pediatric rhabdomyolysis with the published data for adults; (2) determine predictors of acute renal failure in pediatric patients with rhabdomyolysis; and (3) explore the relationship of acute renal failure with treatment modalities such as fluid and bicarbonate administration. METHODS. We performed a retrospective chart review to identify patients with creatinine kinase levels of >1000 IU/L who were treated in the emergency department of a tertiary pediatric hospital between 1993 and 2003, and we constructed regression models. RESULTS. Two hundred ten patients were studied. One hundred ninety-one patients met study eligibility (128 male and 63 female), with a median age of 11 years. The most common documented symptoms were muscle pain (45%), fever (40%), and symptoms of viral infection (39%). The most common causes of pediatric rhabdomyolysis were viral myositis (38%), trauma (26%), and connective tissue disease (5%). Six of 37 patients with creatinine kinase levels of ≥6000 IU/L had previously undiagnosed dermatomyositis or hereditary metabolic disease, compared with 10 of 154 patients with creatinine kinase levels of 1000 to 5999 IU/L. Nine of 191 patients developed acute renal failure. None of 99 patients with initial urinary heme dipstick results of CONCLUSIONS. The cause of acute pediatric rhabdomyolysis is different from that of adult rhabdomyolysis. The risk of acute renal failure in children is much less than the risk reported for adults.

183 citations

Journal ArticleDOI
TL;DR: In the United States rhabdomyolysis is commonly diagnosed in intoxicated patients subjected to prolonged muscle compression as they lay motionless and in patients with seizure disorders, and less frequently, surgeons treat patients who develop rhab Domolysis after crush or other traumatic injury to skeletal muscle.
Abstract: The Old Testament contains the oldest written description of rhabdomyolysis. As the Israelites wandered the desert, they encountered a quail migration and gathered birds to dry and store. Consuming large numbers of quail the people were stricken with “. . . a very great plague . . .” (Numbers 11:33). Ouzounellis postulates that quail consumption produces rhabdomyolysis and myoglobinuric renal failure. The mechanism is apparently analogous to the sensitivity of certain individuals with glucose-6phosphatase deficiency who develop hemolysis after fava bean ingestion. Studies of rhabdomyolysis were published in the German literature in the late 1800s. In 1911 MeyerBetz described a clinical syndrome consisting of dark brown urine, muscle pain, and weakness. Bywaters and Beall reported on the clinical association between crush injury, dark urine, shock, and renal failure in casualties who were crushed beneath fallen masonry for extended periods during the bombing of London during World War II (Fig. 1). Myoglobin present in the urine of these patients was responsible for the dark urinary pigmentation. Recently, casualties with rhabdomyolysis have been generated in large numbers by catastrophes such as mine collapse, train accidents, and seismic events. In the United States rhabdomyolysis is commonly diagnosed in intoxicated patients subjected to prolonged muscle compression as they lay motionless and in patients with seizure disorders. Less frequently, surgeons treat patients who develop rhabdomyolysis after crush or other traumatic injury to skeletal muscle. Renal failure is a well-documented sequellae of rhabdomyolysis. In recent reports, the risk of acute renal failure after rhabdomyolysis ranges from 4% to 33%. Rhabdomyolysis is responsible for 5–7% of all cases of acute renal failure in the United States.

173 citations

References
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Journal ArticleDOI
TL;DR: On the basis of the assumed theory the rate of the observed reaction is directly proportional to the concentration of the enzyme-substrate compound, where (E:l = (ES).
Abstract: On the basis of the assumed theory the rate of the observed reaction is directly proportional to the concentration of the enzyme-substrate compound, (ES), a t all values of the concentration of the substrate, (S). It is proportional to (S) only a t low values of (S). The numerical value of the dissociation constant is given by the substrate concentration a t half-maximum velocity, where (E:l = (ES). The equilibrium in equation 1 may be heterogeneous or homogeneous. Hitchcock'\" has pointed

11,349 citations


"Evaluation of the renal toxicity of..." refers background or methods in this paper

  • ...In the studies performed to determine the type of inhibition produced by ferrihemate, the "active" transport of hippurate was studied and the data were plotted against the hippurate concentration in the media in the manner of Lineweaver and Burk (33)....

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  • ...B. Lineweaver-Burk plot of hippuric acid (0.9 m~) inhibition as a function of p-aminohippurate concentration. determine whether the inhibition from ferrihemate could be overcome....

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  • ...A. Lineweaver-Burk plot of ferrihemate (40 mg/100 ml) inhibition as a function of hippurate concentration....

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  • ...When hippurate uptake is studied in the presence of ferrihemate and a known competitive inhibitor, the Lineweaver-Burk plots of the kinetics are not similar for the two substances....

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  • ...6 A the plot for "active" hippurate transport in the presence of ferrihemate was typical of noncompetit ive inhibit ion (33)....

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Journal ArticleDOI
22 Mar 1941-BMJ
TL;DR: Amongst air-raid casualties seen at this hospital have been four cases of crush injury of the limbs which, because of the general similarity of their clinical course, were thought to represent a specific and hitherto unreported syndrome, and one which has been and will be seen elsewhere during the war.
Abstract: Amongst air-raid casualties seen at this hospital have been four cases of crush injury of the limbs which, because of the general similarity of their clinical course, were thought to represent a specic and hitherto unreported syndrome, and one which has been and will be seen elsewhere during .the war. Suich a condition may have been ob2 0 OScitur. served incLvil l t _ practice, bitt we l ° s .n have been unable to find any ° IIt(, t account of it in the literature. 90 .4The cases are of interest on H c aCCOuint of the H u8 j problem pro% pounded by both 70 pathogenesis and treatment. The picture presented 20 by these four o cases, and substantiated by ' | others, is briefly H68 as follows: 0

794 citations


"Evaluation of the renal toxicity of..." refers background in this paper

  • ...In many clinical settings acute tubule necrosis is temporally related to breakdown of blood or destruction of tissue (1-6)....

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Journal ArticleDOI

524 citations


"Evaluation of the renal toxicity of..." refers background in this paper

  • ...Suggestions made include the following: (a) heine proteins form casts tha t plug tubules and damage cells (13-17); (b) heme proteins either cause or are associated with decreased renal blood flow, and the resultant ischemia leads to acute tubule necrosis (18, 19); and (c) heme proteins or some breakdown products directly injure tubules (12, 13, 20, 21)....

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Journal ArticleDOI

425 citations


"Evaluation of the renal toxicity of..." refers methods in this paper

  • ...The medium was a bicarbonate-buffered Ringer's solution (28)....

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Journal ArticleDOI
TL;DR: The present paper is concerned with the development of a technique and with preliminary observations on the cellular transport of p-aminohippurate (PAH), and found that this technique can be readily adapted to the study of certain renal transport mechanisms.
Abstract: I NVESTIGATIONS on the biochemical mechanisms involved in active renal tubular transport are difficult to approach with the various experimental techniques now available. The study of isolated enzyme systems can at best present only a fragmentary picture of a complex physiological process. The clearance technique, while permitting precise measurement of certain tubular activities throws little light on the nature of the underlying chemical events and, in addition, is handicapped by certain limitations inherent in intact animal experimentation. Consequently, there is a need for simple experimental procedures which will permit a>, the observation of events which accurately reflect tubular transport, b) the simultaneous measurement of certain metabolic activities, and c) the variation of experimental conditions over a broader range than can be achieved in the intact animals. The present paper is concerned with the development of such a technique and with preliminary observations on the cellular transport of p-aminohippurate (PAH). The procedure described in this paper is an outgrowth of several previously employed. Chambers and his associates (I) have observed microscopically the transport of phenol red into the tissue-cultured cysts of embryo chick mesonephros and have reported on the effects of several metabolic inhibitors on this process. Forster (2) has since devised a somewhat simpler procedure utilizing the thin kidney slices or isolated renal tubules of various cold blooded animals. The first paper of this series (3) dealt with observations obtained with this technique. Unfortunately, such studies depend upon the frequent, direct visualization of the kidney tissue and are necessarily limited to colored compounds. More recently, Stern et al. (4) have shown that brain slices, incubated in a saline medium in the Warburg apparatus, are capable of accumulating glutamate against a considerable concentration gradient. We have found that this technique can be readily adapted to the study of certain renal transport mechanisms.

401 citations


"Evaluation of the renal toxicity of..." refers background in this paper

  • ...0 ml of Cross and Taggart's medium (26), with a final pH of 7....

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